Differential effect of cyclooxygenase metabolites on proinflammatory cytokine release by Kupffer cells after liver ischemia and reperfusion

BACKGROUND: Liver ischemia and reperfusion (I/R) induce Kupffer cell (KC) activation with increased release of proinflammatory cytokines. Prostaglandins are potent counterregulatory mediators to control the production of cytokines by macrophages. METHODS: TO study the role of cyclooxygenase metabolites for the release of proinflammatory cytokines by KC in liver I/R, Sprague-Dawley rats were subjected to 20-minute global hepatic ischemia and 60 minutes of reperfusion, Sham-operated animals were used as controls. Kinetics of spontaneous and lipopolysaccharide (LPS)-induced release of proinflammatory cytokines and prostaglandin E-2 (PGE(2)) by KC were assessed both in the presence and absence of the cyclo-oxygenase oxygenase inhibitor ibuprofen, RESULTS: Early after liver I/R (4, 16 hours) the spontaneous secretion of TNF-alpha (+1,058%), IL-1 alpha (+152%),and IL-6 (+161%) by KC was increased (P <0.05), while PGE(2) release in the I/R group was reduced by 51% (P <0.05) in comparison with the sham-operated group, Increased release of PGE(2) in the later period (32 hours) after I/R was associated with decreased TNF-alpha release by KC, Inhibition of PGE(2) production by ibuprofen induced a prolonged and enhanced production of TNF-alpha, while the release of IL-1 alpha and IL-6 was not affected. CONCLUSIONS: Liver I/R leads to a temporary suppression of PGE(2) release by KC, while the release of TNF-alpha is increased. Thus, during early reperfusion, excessive secretion of TNF-alpha by KC may be the result of the absent negative feedback control of cyclooxygenase metabolites. (C) 1998 by Excerpta Medica, Inc.